Pneumococcal diversity: considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA).

Streptococcus pneumoniae is a problematic infectious agent, whose seriousness to human health has been underscored by the recent rise in the frequency of isolation of multidrug-resistant strains. Pneumococcal pneumonia in the elderly is common and often fatal. Young children in the developing world are at significant risk for fatal pneumococcal respiratory disease, while in the developed world otitis media in children results in substantial economic costs. Immunocompromised patients are extremely susceptible to pneumococcal infection. With 90 different capsular types thus far described, the diversity of pneumococci contributes to the challenges of preventing and treating S. pneumoniae infections. The current capsular polysaccharide vaccine is not recommended for use in children younger than 2 years and is not fully effective in the elderly. Therefore, innovative vaccine strategies to protect against this agent are needed. Given the immunogenic nature of S. pneumoniae proteins, these molecules are being investigated as potential vaccine candidates. Pneumococcal surface protein A (PspA) has been evaluated for its ability to elicit protection against S. pneumoniae infection in mouse models of systemic and local disease. This review focuses on immune system responsiveness to PspA and the ability of PspA to elicit cross-protection against heterologous strains. These parameters will be critical to the design of broadly protective pneumococcal vaccines.

Systemic and mucosal protective immunity to pneumococcal surface protein A.

To date our studies demonstrate that PspA is a highly immunogenic molecule in mice and that it can elicit immunity to otherwise fatal infections following iv, ip, in, and it challenge. Although the molecule is serologically variable, it is sufficiently cross-reactive so that immunization with a single PspA can protect against strains of highly diverse serotypes. It is anticipated that a vaccine composed of a mixture of carefully chosen PspA molecules will be able to elicit protective immunity to virtually all pneumococci. If this vaccine proved efficacious in man, it would provide a more simple and less costly means of immunizing against pneumococcal infection than using recombinant vaccines. This could be especially important in the developing world where the cost of successful vaccines must be no more than pennies per dose. If PspA is found to be less efficacious than capsular polysaccharides, it may be valuable as a protein component of a PS-protein conjugate vaccine. In this capacity, PspA might expand the breath of protection elicited by a vaccine composed of only a few polysaccharide-protein conjugates representing capsule types most commonly associated with infectious pneumococci.

Truncated Streptococcus pneumoniae PspA molecules elicit cross-protective immunity against pneumococcal challenge in mice.

Immunization with pneumococcal surface protein A (PspA) from Streptococcus pneumoniae strain Rx1 cross-protects mice against challenge with diverse pneumococci. Truncated Rx1 PspA, consisting of amino acids 192-588, elicits protection against the mouse-virulent strain WU2. The possibility that homologous regions of other PspAs could also elicit cross-protection was investigated. Oligonucleotide primers designed according to the Rx1 pspA gene sequence were used to amplify chromosomal DNA from 15 diverse pneumococci. Three recombinant PspAs were evaluated for their ability to elicit protection in mice against challenge with 7 strains representing capsular types 3, 4, 5, 6A, and 6B. Two of the three truncated PspAs each elicited cross-protection against 71%-100% of the S. pneumoniae challenge strains examined. These data suggest that this technique may be useful for the generation of diverse PspAs for inclusion in a broadly protective pneumococcal vaccine.

Localization of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260.

Pneumococcal surface protein A (PspA) is a virulence factor of Streptococcus pneumoniae that can elicit a protective antibody response. The pspA gene of strain Rx1 encodes a 65 kDa molecule composed of 588 amino acids. The N-terminal 288 amino acids are highly charged, and predict an alpha-helical coiled-coil protein structure. All monoclonal antibodies (MAbs) to PspA, obtained by screening against whole pneumococci, bind to the alpha-helical region of PspA, suggesting that this region is surface exposed. The C-terminal 217 amino acids of PspA contain the surface anchor of PspA and does not appear to be alpha-helical. In the middle of the molecule is a proline-rich region that is thought to traverse the cell wall. In this study we have mapped the immunogenic epitopes detected by 9 MAbs that were made against strain Rx1 PspA. Five of the MAb also react with the PspA of mouse virulent strain WU2. All epitopes were found in one of two portions of the alpha-helical region. One comprised the first 115 amino acids, and the other was within amino acids 192 and 260. The five MAbs that recognize WU2 PspA, but not the remaining four MAbs, were protective against strain WU2. The epitopes detected by four of the five protective MAbs mapped to region 192 to 260 of Rx1 PspA. The existence of protective epitopes in this region was confirmed by demonstrating that mice immunized with the cloned fragment containing these residues were protected from fatal infection with WU2. Since amino acids 192 to 260 are in the region of PspA anticipated to be adjacent to the cell wall, and probably well covered by capsule, the means by which antibodies to the region lead to protection is not obvious.